Nitrification inhibition heterocycle

Abstract

Heterocyclic alkynes useful for nitrification inhibition and methods of using heterocyclic alkynes for nitrification inhibition and crop yield enhancement are described.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 369,015, filed July 21, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Nitrogen is an essential element for plant health. In growing media (e.g., soil), bound nitrogen for plant nutrition can exist in the form of ammonium compounds or nitrates. The ammonium form of nitrogen is preferred because it is easily taken up by plants. In contrast, nitrate nitrogen must be reduced to ammonium by the plant before it can be utilized, an energetically costly process. Ammoniacal nitrogen, which has a positive charge, is tightly bound to the growing medium. Nitrate nitrogen is negatively charged, water-soluble, not tightly bound to the growing medium, and is easily washed away.

[0003] Ammonia-oxidizing bacteria of the genera Nitrosomonas and Nitrobacter oxidize ammoniacal nitrogen to nitrate nitrogen via nitrite nitrogen. This process is known as nitrification. The extent of nitrification depends on temperature, type of growth medium, pH, moisture content, and biological activity. The nitrification process results in the loss of ammoniacal nitrogen and the formation of nitrate nitrogen. As much as half of applied nitrogen fertilizer is lost within a year, and this process contributes to undesirable concentrations of nitrate in groundwater. Therefore, suppression of nitrification is particularly important, and it is generally considered important to selectively inhibit the growth of the above-mentioned bacterial strains.

[0004] The inclusion of certain compounds in critical amounts in growing media is known to have a significant effect on nitrification (the conversion of reduced nitrogen, such as ammonia and ammonium ions, to more oxidized forms, particularly the nitrate form). Prevention of such nitrification in growing media is known to be beneficial and desirable from an economic and agricultural standpoint, as it promotes plant health, increases crop yields, and reduces nitrate runoff.

[0005] Many nitrification inhibitors are known, including linoleic acid, α-linoleic acid, methyl-p-coumarate, methyl ferulate, MHPP, karanjin, brachialactone, 2-chloro-6-trichloromethylpyridine (nitrapyrin), dicyandiamide, 3,4-dimethylpyrazole phosphate, 4-amino-1,2,4-triazole hydrochloride, 1-amido-2-thiourea, 2-amino-4-chloro-6-methylpyrimidine, 5-ethoxy-3-trichloromethyl-1,2,4-thiodiazole, 2-sulfanilamidothiazole, and 3,5-dimethyltetrahydro-1,3,5-thiadiazine-2-thione (dazomet).

[0006] Nitrification inhibition is disclosed in the following publications: U.S. Pat. Nos. 3,494,757 and 3,635,690, German Patent Application Publication No. 2,745,833, and British Patent No. 1,592,516, as well as U.S. Pat. No. 3,050,380 to Goring, British Patent No. 970,663 to Watkins, U.K. Patent No. 3,533,774 to Nault, U.S. Pat. No. 4,673,429 to Rieber et al., U.S. Pat. No. 4,925,476 to Wagner et al., U.S. Pat. No. 2015 / 0052960 to Makin et al., and U.S. Pat. No. 2017 / 0052960 to Nave et al. See also U.S. Patent Application Publication No. 36969 to Cunningham et al.; U.S. Patent Application Publication No. 2020 / 0352162 to Nave et al.; WO 2015 / 158853 to Nave et al.; WO 2020 / 002472 to Cunningham et al.; WO 2020 / 020765 to Nesvadba et al.; WO 2020 / 020777 to Nesvadba et al. The disclosures of these references and other references cited in this application are incorporated herein by reference in their entirety.

[0007] Some conventional nitrification inhibitors do not have properties that are beneficial to the user, for example, dazomet has a highly non-specific action and is known to attack non-target bacteria in the growth medium, especially in soil.

[0008] There remains a need for nitrification inhibitors that exhibit nitrification inhibition without less beneficial characteristics. Summary of the Invention

[0009] Certain alkynyl heterocycles have been found to be useful in controlling nitrification. Specifically, certain ethynylthiazoles, ethynyloxazoles, and ethynylisoxazoles have been found to inhibit nitrification. Such inhibition is useful because it promotes more efficient nitrogen uptake by plants and increases crop yields. Nitrification inhibition is also useful for reducing nitrate production in growing media, particularly soil, thereby reducing the amount of undesirable nitrates in groundwater.

[0010] Methods for using the compounds include applying and / or incorporating into the growing medium (e.g., soil) an effective amount of a nitrification-inhibiting alkynyl heterocycle. Preferred compounds include ethynylthiazole, ethynyloxazole, ethynylisoxazole, or mixtures thereof. DETAILED DESCRIPTION OF THE INVENTION

[0011] As used herein, growing medium is defined as the material in which plants are grown. Exemplary growing media include, but are not limited to, soil, perlite, pumice, vermiculite, zeolite, compost, peat moss, coconut coir, sand, silt, clay, water, bark, sawdust, water, and limestone. Exemplary growing media may be outdoor soil-based or hydroponic.

[0012] As used herein, alkyl refers to a C1 to C6 branched or unbranched group consisting of carbon atoms and hydrogen atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

[0013] As used herein, alkoxy refers to an O-C1-C6 group in which an oxygen atom is bonded to a C1-C6 branched or unbranched alkyl group. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0014] As used herein, thioalkyl refers to a branched or unbranched S-C1-C6 group in which a sulfur atom is bonded to a C1-C6 alkyl group. Examples of thioalkyl groups include thiomethyl, thioethyl, thiopropyl, thioisopropyl, thiobutyl, thioisobutyl, thiosecbutyl, and thiotertbutyl.

[0015] As used herein, cycloalkyl refers to a C3-C6 group in which the carbon atoms form a carbocyclic ring. Examples of cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like.

[0016] As used herein, alkenyl refers to a branched or unbranched C2-C6 group consisting of carbon and hydrogen atoms and having one or more double bonds between carbon atoms. Examples of alkenyl groups include ethylene, propene, 1-butene, 2-butene, and isobutene.

[0017] As used herein, cycloalkenyl refers to a carbon ring having carbon atoms of C3 to C6 containing one or two double bonds. Examples of cycloalkenyl groups include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cyclopentadiene, and 1,4-cyclohexadiene.

[0018] As used herein, halo refers to halogen atoms such as F, Cl, Br, and I.

[0019] As used herein, haloalkyl refers to a C1-C6 branched or unbranched alkyl group in which one or more hydrogen atoms have been replaced by halogen atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl, bromoethyl, iodobutyl, and dichloroethyl.

[0020] As used herein, haloalkoxy refers to a C1-C6 group in which an oxygen atom is bonded to a C1-C6 branched or unbranched alkyl group in which one or more hydrogen atoms have been replaced by halogen atoms. Examples of halokoxy groups include trifluoromethoxy, difluoroethoxy, chloropropoxy, bromoisopropoxy, and dibromobutoxy.

[0021] As used herein, haloalkenyl refers to a C2-C6 branched or unbranched group consisting of carbon and hydrogen atoms, in which one or more hydrogen atoms have been replaced by halogen atoms and which has one or more double bonds between carbon atoms. Examples of haloalkenyl groups include 1-chloroethylene, 3,3-difluoropropene, and 4-bromo-1-butene.

[0022] The term N-oxide includes any compound having at least one tertiary nitrogen atom oxidized to an N-oxide moiety. N-oxides can be formed, for example, by oxidation of tertiary amines, such as pyridine, with hydrogen peroxide.

[0023] Salts and agriculturally acceptable salts as used herein include hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, nitrates, hydrogensulfates, sulfates, dihydrogenphosphates, hydrogenphosphates, phosphates, carbonates, bicarbonates, oxalates, and C1-C6 branched or unbranched alkanoates (such as formates, acetates, n-propionates, i-propionates).

[0024] Carriers used herein include liquid or solid carriers. In some embodiments, carriers can include organic or inorganic carriers. Exemplary liquid carriers include, but are not limited to, water; petroleum fractions or hydrocarbons such as mineral oil, aromatic solvents, and paraffin oil; vegetable oils such as soybean oil, rapeseed oil, olive oil, castor oil, sunflower seed oil, coconut oil, corn oil, cottonseed oil, linseed oil, palm oil, peanut oil, safflower oil, sesame oil, and tung oil; esters of the above vegetable oils; monoalcohols or dihydric, trihydric, or other lower polyalcohols (4-6), such as 2-ethylhexyl stearate, n-butyl oleate, isopropyl myristate, propylene glycol dioleate, dioctyl succinate, dibutyl adipate, and dioctyl phthalate. esters of mono-, di-, and polycarboxylic acids and the like; toluene; xylene; petroleum naphtha; crop oils; acetone; methyl ethyl ketone; cyclohexanone; trichloroethylene; perchloroethylene; ethyl acetate; amyl acetate; butyl acetate; propylene glycol monomethyl ether and diethylene glycol monomethyl ether; methyl alcohol; ethyl alcohol; isopropyl alcohol; amyl alcohol; ethylene glycol; propylene glycol; glycerin; N-methyl-2-pyrrolidinone; N;N-dimethylalkylamides; dimethyl sulfoxide; and liquid fertilizers; and mixtures thereof. Exemplary solid carriers include, but are not limited to, silica, silica gel, silicates, talc, kaolin, limestone, lime, chalk, ball clay, loess, clay, dolomite, diatomaceous earth, calcium sulfate, magnesium sulfate, magnesium oxide, ground synthetic materials, pyrophyllite clay, attapulgaceous clay, kieselguhr, calcium carbonate, bentonite clay, fuller's earth, cottonseed hulls, wheat flour, soybean flour, pumice, wood flour, walnut shell flour, lignin, ammonium sulfate, ammonium phosphate, ammonium nitrate, urea, grain flour, bark flour, wood flour, nut shell flour, cellulose powder, and mixtures thereof. Fertilizers, such as, but not limited to, fertilizers containing ammonia, may also be used as carriers.Exemplary fertilizers include, but are not limited to, anhydrous ammonium; ammonium salts such as ammonium nitrate, calcium ammonium nitrate, ammonium nitrate sulfate, ammonium sulfate, or ammonium phosphate; organic ammonia sources such as manure, biogas, worm castings, compost, seaweed, or guano; and urea-containing fertilizers such as urea, formaldehyde urea, urea ammonium nitrate solution, urea sulfur, urea ammonium sulfate, or other urea-based fertilizers.

[0025] The surfactant or surfactants (e.g., wetting agent, tackifier, dispersant, emulsifier) used herein include, but are not limited to, alkali metal, alkaline earth metal, and ammonium salts of fatty or aromatic sulfonic acids (e.g., lignosulfonic acid, phenolsulfonic acid, naphthalenesulfonic acid, and dibutylnaphthalenesulfonic acid); alkyl and alkylaryl sulfonates; alkyl sulfates, lauryl ether sulfates, and fatty alcohol sulfates; salts of sulfated hexa-, hepta-, and octadecanol; salts of fatty alcohol glycol ethers; condensation products of sulfonated naphthalene and its derivatives with formaldehyde; condensation products of naphthalene or naphthalenesulfonic acid with phenol and formaldehyde; polyoxyethylene olefins; ethoxylated isooctyl-, octyl-, or nonylphenol, alkylphenyl, or tributylphenyl polyglycol ethers; alkylaryl polyether alcohols; isotridecyl alcohol; fatty alcohol / ethylene oxide condensates; ethoxylated castor oil; polyoxyethylene alkyl ethers or polyoxypropylene alkyl ethers; lauryl alcohol polyglycol ether acetate; sorbitol esters; lignosulfite waste liquors and proteins; modified proteins; polysaccharides (e.g., methylcellulose); hydrophobically modified starches; and polyvinyl alcohols, polycarboxylates, polyalkoxylates, polyvinylamines, polyethyleneimines, polyvinylpyrrolidones, and copolymers thereof.

[0026] Adjuvants, as used herein, include agriculturally acceptable adjuvants. Exemplary agriculturally acceptable adjuvants include, but are not limited to, antifreeze agents, antifoam agents, compatibilizers, sequestering agents, neutralizing and buffering agents, corrosion inhibitors, colorants, odorants, penetration aids, wetting agents, spreading agents, dispersing agents, thickeners, freezing point depressants, antimicrobial agents, crop oils (concentrates), adhesives (e.g., for use in seed treatment formulations), surfactants, protective colloids, emulsifiers, tackifiers, and mixtures thereof.

[0027] Exemplary agriculturally acceptable adjuvants include, but are not limited to, crop oil concentrates (e.g., 85% mineral oil + 15% emulsifier); nonylphenol ethoxylates; benzyl cocoalkyldimethyl quaternary ammonium salts; blends of petroleum hydrocarbons, alkyl esters, organic acids, and anionic surfactants; C9-C 11 Alkyl polyglycosides; Phosphorylated alcohol ethoxylates; Natural primary alcohols (C 12 ~C 16 ) ethoxylate; di-sec-butylphenol EO-PO block copolymer; polysiloxane-methyl capped; nonylphenol ethoxylate + urea ammonium nitrate; emulsified methylated seed oil; tridecyl alcohol (synthetic) ethoxylate (e.g., 8EO); tallow amine ethoxylate (e.g., 15EO); and PEG(400) dioleate-99.

[0028] Exemplary agriculturally acceptable adjuvants include, but are not limited to, thickeners (i.e., thickeners). Exemplary thickeners include, but are not limited to, polysaccharides (e.g., xanthan gum), organic and inorganic sheet minerals, and mixtures thereof.

[0029] Exemplary agriculturally acceptable adjuvants include, but are not limited to, antifoaming agents, including, but not limited to, silicone emulsions, long chain alcohols, fatty acids, fatty acid salts, organofluorine compounds, and mixtures thereof.

[0030] Exemplary agriculturally acceptable adjuvants include, but are not limited to, antifreeze agents, including, but not limited to, ethylene glycol, propylene glycol, urea, glycerol, and mixtures thereof.

[0031] Exemplary agriculturally acceptable adjuvants include, but are not limited to, colorants. Exemplary colorants include, but are not limited to, the dyes known as Rhodamine B, Pigment Blue 15:4, Pigment Blue 15:3, Pigment Blue 15:2, Pigment Blue 15:1, Pigment Blue 80, Pigment Yellow 1, Pigment Yellow 13, Pigment Red 112, Pigment Red 48:2, Pigment Red 48:1, Pigment Red 57:1, Pigment Red 53:1, Pigment Orange 43, Pigment Orange 34, Pigment Orange 5, Pigment Green 36, Pigment Green 7, Pigment White 6, Pigment Brown 25, Basic Violet 10, Basic Violet 49, Acid Red 51, Acid Red 52, Acid Red 14, Acid Blue 9, Acid Yellow 23, Basic Red 10, Basic Red 108, and mixtures thereof.

[0032] Exemplary agriculturally acceptable adjuvants include, but are not limited to, adhesives, including, but not limited to, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, tylose, and mixtures thereof.

[0033] As used herein, an agriculturally effective amount of a compound is an amount of compound that has a measurable effect on one or more of ammonium nitrogen, nitrification inhibition, nitrate formation, improved plant health, increased plant growth, increased plant or crop yield, bacteria of the genera Nitrosomonas and Nitrobacter.

[0034] As used herein, "compound" or "compounds" includes chemical compounds defined by molecular formula and / or chemical name, as well as their tautomers, salts, N-oxides, and stereoisomers.

[0035] The compounds described herein are nitrification inhibitors. One or more compounds described herein may be formulated into compositions containing other ingredients, such as carriers, surfactants, and adjuvants. The compositions may optionally include an ammonia source. To enhance plant health and / or improve crop yield, the compounds or compositions can be applied to growing media with or without an ammonia source. Ammonia sources include anhydrous ammonia, urea, urea-ammonium nitrate, and compost. The compounds or compositions can be mixed directly with the ammonia source. A mixture of the compounds or compositions and the ammonia source can be applied directly to a growing medium, such as soil. The compounds or compositions and the ammonia source can be applied separately to a growing medium, such as soil. The compounds or compositions and the ammonia source can be applied separately and simultaneously.

[0036] The compound or composition and the ammonia source may be applied separately and sequentially. The sequential application of the compound or composition and the ammonia source may be within 24 hours, within 1 to 3 days, within 1 to 5 days, within 1 week, within 2 weeks, within 3 weeks, or within 4 weeks; within 1 to 2 weeks, within 1 to 3 weeks, or within 1 to 4 weeks; within 2 to 3 weeks, or within 2 to 4 weeks. The compound or composition may be applied before or after planting. The compound or composition may be applied before or after emergence.

[0037] In certain aspects, the nitrification inhibition compositions or methods provided herein include one or more of the following compounds and agriculturally acceptable salts, tautomers, stereoisomers, and N-oxides thereof: [ka] (In these formulas, R1 to R4 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 thioalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkenyl, C3-C6 cycloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH( CH3)C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C≡CCH3, C(=O)C≡C, C(=O)N(CH3)CH3, and at least one of R1-R4 is C≡C or C≡C-TMS; [ka] (In these formulas, R1 to R4 are independently H, C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, vinyl, and at least one of R1 to R4 is C≡C or C≡C-TMS; [ka] (In the formula, R 11 ~R 14are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 thioalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkenyl, C3-C6 cycloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH 3) C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and R 11 ~R 14 at least one of which is C≡C or C≡C-TMS); [ka] (In the formula, R 11 and R 14 are independently C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, and vinyl; R 11 and R 14 at least one of R is C≡C or C≡C-TMS; 12 ~R 13 is H); [ka] (In the formula, R 21 ~R 24are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 thioalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkenyl, C3-C6 cycloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH 3) C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and R 21 ~R 24 at least one of which is C≡C or C≡C-TMS); [ka] (In the formula, R 21 and R 24 are independently C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, and vinyl; R 21 and R 24 at least one of R is C≡C or C≡C-TMS; 22 , R 23 , and R 25 is H); [ka] (In the formula, R 31 ~R34 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 thioalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkenyl, C3-C6 cycloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH 3) C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and R 31 ~R 34 at least one of which is C≡C or C≡C-TMS); [ka] (In the formula, R 31 and R 33 are independently C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, and vinyl; R 31 and R 33 at least one of R is C≡C or C≡C-TMS; 32 and R 34 is H); [ka] (In the formula, R 41 ~R44 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 thioalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkenyl, C3-C6 cycloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH 3) C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and R 41 ~R 44 at least one of which is C≡C or C≡C-TMS); [ka] (In the formula, R 41 and R 43 are independently C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, and vinyl; R 41 and R 43 at least one of R is C≡C or C≡C-TMS; 42 and R 44 is H); [ka] (In the formula, R 51 , R52 , and R 53 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 thioalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkenyl, C3-C6 cycloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH 3) C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and R 51 , R 52 , or R 53 at least one of which is C≡C or C≡C-TMS); [ka] (In the formula, R 51 , R 52 , and R 53 are independently H, C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, and vinyl; R 51 , R 52 , or R 53 at least one of which is C≡C or C≡C-TMS); [ka] (In the formula, R 61 , R 62 , and R 63 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 thioalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkenyl, C3-C6 cycloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH 3) C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and R 61 , R 62 , or R 63 at least one of which is C≡C or C≡C-TMS); [ka] (In the formula, R 61 , R 62 , and R 63 are independently H, C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, and vinyl; R 61 , R 62 , or R 63 at least one of which is C≡C or C≡C-TMS); [ka] (In the formula, R 71 , R 72 , R 73 , and R 74 are independently H, ethynyl, trimethylsilyl-ethynyl, C1-C6 alkoxy, C1-C6 thioalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkenyl, C3-C6 cycloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, benzyl, CH(OH)CH3, C(=O)NH2, CO2H, CO2Me, CO2Et, C(=O)H, CH2OH, halogen, C(=O)NHCH2C≡C, C(=O)NHCH(CH 3) C≡C, C(=O)NHCH(CH2CH3)C≡C, C≡N, C(=O)NHC(CH3)(CH3)C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH3)CH3, C(=O)NHCH(CH3)CH2CH3, C(=O)NHCH(CH2CH3)CH2CH3, C(=O)alkyl, C(=O)haloalkyl, C(=O)CH3, C(=O)Et, C(=O)C=CCH3, C(=O) C≡C, C(=O)N(CH3)CH3, and R 71 , R 72 , R 73 , or R 74 at least one of which is C≡C or C≡C-TMS); [ka] (In the formula, R 71 , R 72 , R 73 , and R 74 are independently H, C≡C, C≡C-TMS, C≡CMe, OEt, OMe, OCF3, OH, I, Cl, F, methyl, ethyl, cyclopropyl, propyl, SMe, CN, benzyl, acetyl, and vinyl; R 71 , R 72 , R 73 , or R 74at least one of which is C≡C or C≡C-TMS).

[0038] In certain aspects, the nitrification-inhibiting compounds, compositions, or methods provided herein comprise a compound selected from the group consisting of: [ka] [ka] [ka] and agriculturally acceptable salts, N-oxides, stereoisomers, and tautomers thereof.

[0039] In certain aspects, the nitrification-inhibiting compounds, compositions, or methods provided herein comprise a compound selected from the group consisting of: [ka] and agriculturally acceptable salts, N-oxides, stereoisomers, and tautomers thereof.

[0040] In certain embodiments, the nitrification-inhibiting compound is selected from the group consisting of the compounds in Table 1, and agriculturally acceptable salts, N-oxides, stereoisomers, and tautomers thereof.

[0041] Soil application of nitrification inhibitor compounds. In certain embodiments provided herein, one or more nitrification inhibitor compounds or compositions are mixed with an ammonia source, including, but not limited to, anhydrous ammonium; ammonium salts such as ammonium nitrate, calcium ammonium nitrate, ammonium nitrate sulfate, ammonium sulfate, or ammonium phosphate; organic ammonia sources such as manure, biogas, worm castings, compost, seaweed, or guano; or urea-containing fertilizers such as urea, formaldehyde urea, urea ammonium nitrate solution, urea sulfur, urea ammonium sulfate, or other urea-based fertilizers.

[0042] In certain embodiments provided herein, one or more nitrification inhibitor compounds or compositions are mixed with anhydrous ammonia, which is then injected into the soil. In other embodiments, the compounds or compositions are injected separately into the growing medium at the time of anhydrous ammonia application. The amount of compound or composition present in the anhydrous ammonia mixture or injected directly can be adjusted so that an agriculturally effective amount of the nitrification inhibitor compound or composition is applied.

[0043] In certain aspects provided herein, a nitrification inhibitor compound or composition is mixed with a fertilizer, such as a urea-ammonium nitrate solution, to form a urea-ammonium nitrate nitrification inhibitor mixture.

[0044] These mixtures may also contain other ingredients, such as herbicides, insecticides, fungicides, and safeners. Such mixtures may be applied at rates of about 10 to about 70 gallons per acre, depending on the strength and concentration of the fertilizer and the target amount of nitrogen per acre. For example, the amount of compound or composition present in the treated mixture may be adjusted so that an agriculturally effective amount of the compound or composition is applied.

[0045] In certain embodiments provided herein, the nitrifying compound or composition is impregnated into dry urea. The amount of the compound or composition impregnated depends on the application rate of the urea. For example, urea can be applied at a rate of about 200 to about 700 pounds per acre. A certain amount of the compound or composition may be impregnated into the dry urea so that the compound or composition is applied in an agriculturally effective amount.

[0046] In certain aspects provided herein, the compound or composition is applied as part of a manure slurry mixture. The compound or composition may be mixed with the manure before application or may be applied separately. The amount of compound or composition present in the manure slurry may be adjusted so that an agriculturally effective amount of the compound or composition is applied.

[0047] The compound or composition can be applied to the growing medium at a rate of about 50 grams to about 4 kilograms per acre. The compound can be applied to the growing medium at the following rates: 50-60 grams / acre; 60-70 grams / acre; 70-80 grams / acre; 80-90 grams / acre; 90-100 grams / acre; 100-120 grams / acre; 120-140 grams / acre; 140-160 grams / acre; 160-180 grams / acre; 180-200 grams / acre; 200-225 grams / acre; 225-250 grams / acre; 250-275 grams / acre; 275-300 grams / acre; 300-350 grams / acre; 350-400 grams / acre; 400-450 grams / acre; 450-500 grams / acre; 500-550 grams / acre; 550-600 grams / acre; 600-650 grams / acre; 650-700 grams / acre; 700-750 grams / acre; 750-800 grams / acre; 800-850 grams / acre -;850-900 grams / acre;900-950 grams / acre;950-1000 grams / acre;1.0-1.1 kilograms / acre;1.1-1.2 kilograms / acre;1.2-1.3 kilograms / acre;1.3-1.4 kilograms / acre;1.4-1.5 kilograms / acre;1.5-1.6 kilograms / acre;1.6-1.7 kilograms / acre;1.7-1.8 kilograms / acre;1.8-1.9 kilograms m / acre; 1.9 to 2.0 kilograms / acre; 2.0 to 2.2 kilograms / acre; 2.2 to 2.4 kilograms / acre; 2.4 to 2.6 kilograms / acre; 2.6 to 2.8 kilograms / acre; 2.8 to 3.0 kilograms / acre; 3.0 to 3.2 kilograms / acre; 3.2 to 3.4 kilograms / acre; 3.4 to 3.6 kilograms / acre; 3.6 to 3.8 kilograms / acre; and 3.8 to 4.0 kilograms / acre. [Example]

[0048] Basic synthesis procedure Basic Step 1 To a stirred solution (0.2 mmol) of the heterocycle (1 equiv., 0.7 g, 3.95 mmol) in EtOAc, TEA (4 equiv.) and CuI (5 mol%) were added at RT. The reaction mixture was degassed with argon for 5 min, followed by the addition of TMS-acetylene (4.5 equiv.) and bis(triphenylphosphine)palladium chloride (15 mol%). The reaction mixture was stirred at 50 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite pad, and the filtrate was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 10–20% EtOAc in petroleum ether to give the desired product.

[0049] Basic Step 2 To a stirring solution (0.2 mmol) of ethynyl TMS heterocycle (1.0 equiv.) in methanol was added 1 equiv. of potassium carbonate. The reaction was stirred at room temperature until completion (monitored by TLC). The reaction mixture was filtered through a pad of Celite, and the filtrate was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 10-20% EtOAc in petroleum ether to give the desired product.

[0050] Basic Step 3 The aldehyde (1.0 equiv.) was dissolved in anhydrous methanol (0.2–0.5 mM), charged with cesium carbonate (1.0 equiv.), and cooled to 0–5°C. Dimethyl (l-diazo-2-oxopropyl)phosphonate (1.0 equiv.) was added dropwise, and the reaction was then stirred for 1–18 h, after which the crude mixture was concentrated onto silica gel and directly purified by flash silica gel chromatography to afford the desired alkyne.

[0051] Synthesis procedure 12780973 To a degassed solution of methyl 2-bromo-1,3-thiazole-5-carboxylate (500 mg, 2.252 mmol) and EtN (1.4 mL, 9.68 mmol) in EtOH (2.0 mL) was added trimethylsilylacetylene (1.5 mL, 10.81 mmol), bis(triphenylphosphine)palladium(II) chloride (79 mg, 0.113 mmol), and copper(I) iodide (4.29 mg, 0.023 mmol). The mixture was heated at 50 °C for 7 h, then cooled to 25 °C, and the reaction mixture was filtered through Celite. The solvent was removed under reduced pressure to give the desired product.

[0052] 12791843 To a solution of 1-(4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)thiazol-5-yl)ethan-1-one (0.4 g, 1.37 mmol) in MeOH (5 mL) was added NaBH (0.025 g, 0.68 mmol) at 0 °C and stirred at the same temperature for 1 h. Water (10 mL) was added to the reaction mixture, which was then extracted with DCM, washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh) eluting with 20-25% EtOAc in petroleum ether to give 0.2 g (65%) of the desired product as an off-white solid; melting point 73-77 °C. 1 H NMR(400MHz,CDCl3)δ 5.48-5.45(m,1H),3.50(s,1H),2.44-2.43(m,1H),1.60-1.58(m,3H); 19 F NMR(376MHz,CDCl3)δ -60.41;ESIMS m / z 222.07([M+H]+).

[0053] 12791845 To a solution of 4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (0.2 g, 0.68 mmol) in a 3:1 THF-HO mixture (5 mL) was added LiOH·HO (0.03 g, 0.68 mmol), and the reaction mixture was stirred at RT for 2 h. The reaction mixture was acidified with 1 N HCl and extracted with DCM. The organic layer was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh) eluting with 60-70% EtOAc in petroleum ether to give 0.035 g (23%) of the desired light brown solid; melting point 134-138 °C. 1 H NMR(400MHz,DMSO-d6)δ 8.39(s,1H),8.14(s,1H),5.24(s,1H); 19 F NMR(376MHz,CDCl3)δ -60.27;ESIMS m / z 221.06([M+H]+).

[0054] 12791847 To a solution of ethyl 2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (0.1 g, 0.44 mmol) in a 3:1 THF-HO mixture (5 mL) was added LiOH·HO (0.02 g, 0.44 mmol), and the reaction mixture was stirred at RT for 2 h. The reaction mixture was acidified with 1 N HCl and extracted with DCM. The organic layer was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 0.03 g (44%) of the desired product as a light brown solid; melting point 178–182 °C. 1 H NMR(400MHz,DMSO-d6)δ 8.40(s,1H),8.26(s,1H),7.80(s,1H),5.08(s,1H);ESIMS m / z 153.01([M+H]+).

[0055] 12791857 To a solution of 1-(2-ethynylthiazol-5-yl)ethan-1-one (0.1 g, 0.66 mmol) in MeOH (3 mL) was added NaBH (0.013 g, 0.33 mmol) at 0 °C and stirred at the same temperature for 1 h. Water (10 mL) was added to the reaction mixture, which was then extracted with DCM, washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh) eluting with 20-25% EtOAc in petroleum ether to give 0.09 g (89%) of the desired brown solid; melting point 72-76 °C. 1 H NMR(400MHz,CDCl3)δ 7.64(s,1H),5.21-5.15(m,1H),3.45(s,1H),2.20-2.19(m,1H),1.63-1.60(m,3H);ESIMS m / z 154.03([M+H]+).

[0056] 12791863 To a solution of ethyl 2-ethynylthiazole-5-carboxylate (1.4 g, 5.53 mmol) in a 3:1 mixture of THF and HO (15 mL) was added LiOH·HO (0.28 g, 6.64 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was acidified with 1 N HCl (pH ∼2) and extracted with DCM. The organic layer was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 0.8 g (72%) of the desired product as a black solid; melting point 195–199 °C; 1 H NMR(400MHz,DMSO-d6)δ 13.30(brs,1H),8.54(s,1H),5.02(s,1H);ESIMS m / z 153.99([M+H]+).

[0057] 12791865 To a solution of 2-ethynylthiazole-5-carboxylic acid (0.25 g, 1.63 mmol) in DMF (5 mL) was added HATU (0.745 g, 1.96 mmol), DIPEA (0.315 g, 2.45 mmol), and NHCl (0.1 g, 1.96 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc. The organic layer was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh) eluting with 50-60% EtOAc in petroleum ether to give 0.17 g (66%) of the desired product as an off-white solid; melting point 162-166 °C. 1 H NMR(400MHz,DMSO-d6)δ 8.36(s,1H),7.88(s,1H),7.65(s,1H),5.02(s,1H);ESIMS m / z 153.02([M+H]+).

[0058] 12791867 To a solution of 2-ethynylthiazole-4-carboxylic acid (0.25 g, 1.63 mmol) in DMF (5 mL) was added HATU (0.93 g, 2.45 mmol), DIPEA (0.42 g, 3.26 mmol), and 2-methylbut-3-yn-2-amine (0.16 g, 1.96 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh) eluting with 30-40% EtOAc in petroleum ether to give 0.16 g (45%) of the desired product as an off-white solid; melting point 101-105 °C. 1 H NMR(400MHz,CDCl3)δ 8.13(s,1H),7.40(brs,1H),3.53(s,1H),2.38(s,1H),1.76(s,3H),1.75(s,3H);ESIMS m / z 219.07([M+H]+).

[0059] 12791869 To a solution of 2-ethynylthiazole-4-carboxylic acid (0.25 g, 1.63 mmol) in DMF (5 mL) was added HATU (0.93 g, 2.45 mmol), DIPEA (0.42 g, 3.26 mmol), and 2-methylbut-3-yn-2-amine (0.16 g, 1.96 mmol), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc. The organic layer was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh) eluting with 30-40% EtOAc in petroleum ether to give the product as an off-white solid (0.17 g, 54%); melting point 121-125 °C. 1 H NMR(400MHz,CDCl3)δ 8.16(s,1H),7.47(brs,1H),4.25-4.23(m,2H),3.54(s,1H),2.27-2.26(m,1H);ESIMS m / z 191.03([M+H]+).

[0060] 12795389 To a solution of 2-bromo-N-(2-methylbut-3-yn-2-yl)thiazole-4-carboxamide (0.4 g, 1.46 mmol) in toluene (5 mL) was added CuI (0.03 g, 0.14 mmol), followed by DIPEA (0.37 g, 2.93 mmol), PdCl(PPh) (0.05 g, 0.07 mmol), and TMS acetylene (0.18 g, 1.75 mmol) under an argon atmosphere, and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to RT, EtOAc (30 mL) was added, and filtered through a Celite pad. The filtrate was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh) eluting with 5-10% EtOAc in petroleum ether to give 0.12 g (28%) of the desired brown liquid; FT-IR 1666.53 cm -1 (C=O stretch present); 1H NMR(400MHz,CDCl3)δ 8.09(s,1H),7.41(brs,1H),2.38(s,1H),1.74-1.73(m,6H),0.30(s,9H);ESIMS m / z 291.01([M+H]+).

[0061] 12795393 To a solution of 2-bromo-N-(prop-2-yn-1-yl)thiazole-4-carboxamide (0.4 g, 1.46 mmol) in toluene (5 mL) was added CuI (0.03 g, 0.14 mmol), followed by DIPEA (0.37 g, 2.93 mmol), PdCl(PPh) (0.05 g, 0.07 mmol), and TMS acetylene (0.18 g, 1.75 mmol) under an argon atmosphere, and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to RT, EtOAc (30 mL) was added, and filtered through a Celite pad. The filtrate was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh) eluting with 5-10% EtOAc in petroleum ether to give 0.12 g (28%) of the desired pale brown solid (0.11 g, 25%); melting point 79-83 °C; 1 H NMR(400MHz,CDCl3)δ 8.11(s,1H),7.48(brs,1H),4.24-4.21(m,2H),2.26-2.24(m,1H),0.30(s,9H);ESIMS m / z 263.08([M+H]+).

[0062] 12806737 To a stirred solution of 1-(2-((trimethylsilyl)ethynyl)thiazol-4-yl)prop-2-yn-1-one (0.2 g, 0.80 mmol) in MeOH (2 mL) was added K2CO3 (1 mg, catalytic amount) at RT. The reaction mixture was stirred at RT for 5 min. After completion of the reaction, the reaction mixture was poured into ice water (5 mL), acidified with 1 N HCl (2 mL, pH 4), and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using an eluent of 10% EtOAc in petroleum ether to give the product as a light brown solid (0.032 g, 27%); melting point: 126-130 °C. 1 H NMR(400MHz,CDCl3)δ 8.33(s,1H),3.56(s,1H),3.50(s,1H);ESIMS m / z 162.08([M+H]+).

[0063] 12806745 To a stirred solution of (E)-1-(2-((trimethylsilyl)ethynyl)thiazol-4-yl)but-2-en-1-one (0.2 g, 0.80 mmol) in MeOH (2 mL) was added K2CO3 (1 mg, catalytic amount) at RT. The reaction mixture was stirred at RT for 5 min. After completion of the reaction, the reaction mixture was poured into ice water (5 mL), acidified with 1 N HCl (2 mL, pH 4), and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using an eluent of 10% EtOAc in petroleum ether to give a light brown solid (0.025 g, 17%); melting point: 111-115 °C. 1 H NMR(400MHz,CDCl3)δ 8.33(s,1H),7.23-7.14(m,1H),6.77-6.72(m,1H),3.63(s,1H);2.03(t,J=3.4Hz,3H);ESIMS m / z 178.09([M+H]+).

[0064] 12806753 To a stirred solution of 1-(2-((trimethylsilyl)ethynyl)thiazol-5-yl)prop-2-yn-1-one (1.2 g, 5.76 mmol) in DCM (15 mL) was added DMP (3.17 g, 7.49 mmol) at 0° C. The reaction mixture was stirred at RT for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 24 g) using an eluent of 10-20% EtOAc in petroleum ether to give the product as a brown solid (0.2 g, 50%); melting point 78-82° C. 1 H NMR(400MHz,CDCl3)δ 8.50(s,1H),3.45(s,1H),0.30(s,9H);ESIMS m / z 234.11([M+H]+).

[0065] 12806761 To a stirred solution of (E)-1-(2-((trimethylsilyl)ethynyl)thiazol-4-yl)but-2-en-1-one (0.2 g, 0.80 mmol) in MeOH (2 mL) was added K2CO3 (1 mg, catalytic amount) at RT. The reaction mixture was stirred at RT for 5 min. After completion of the reaction, the reaction mixture was poured into ice water (5 mL), acidified with 1 N HCl (2 mL, pH ∼4), and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using an eluent of 10% EtOAc in petroleum ether to give the desired product (0.025 g, 21%) as a light brown solid (0.025 g, 17%); melting point 111–115 °C. 1 H NMR(400MHz,CDCl3)δ 8.33(s,1H),7.23-7.14(m,1H),6.77-6.72(m,1H),3.63(s,1H);2.03(t,J=3.4Hz,3H);ESIMS m / z 178.09([M+H]+).

[0066] 12811457 To N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol) in 3 mL of THF was added 1 mL of MeOH at 0° C., and the reaction was stirred for 30 minutes at 0° C. After completion of the reaction, the mixture was filtered, washed with THF, and the filtrate was concentrated at low temperature to give the product as a yellow solid (40 mg, 86%).

[0067] 12811461 To N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol) in 3 mL of THF was added 1 mL of MeOH at 0° C., and the reaction was stirred for 30 minutes at 0° C. After completion of the reaction, the mixture was filtered, washed with THF, and the filtrate was concentrated at low temperature to give the product as a brown solid (40 mg, 83%).

[0068] 12811465 To trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), and NEt3 (1.5 mL) in 4.5 mL of THF under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidophenyl)benzamide (150 mg, 0.54 mmol) was added. The reaction was stirred at 50 °C for 2 h. After completion of the reaction, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 5:1) to give the product as a yellow solid.

[0069] 12811467 To trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), and NEt3 (1.5 mL) in 4.5 mL of THF under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidophenyl)benzamide (150 mg, 0.54 mmol) was added. The reaction was stirred at 50 °C for 2 h. After completion of the reaction, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 5:1) to give the product as a yellow solid.

[0070] 12811469 To trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), and NEt3 (1.5 mL) in 4.5 mL of THF under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidophenyl)benzamide (150 mg, 0.54 mmol) was added. The reaction was stirred at 50 °C for 2 h. After completion of the reaction, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 5:1) to give the product as a yellow solid.

[0071] 12811471 To a solution of trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), and NEt3 (1.5 mL) in 4.5 mL of THF under N2, 2-bromo-N-methylthiazole-5-carboxamide (0.54 mmol) was added. The reaction was stirred at 50 °C for 2 h. After completion of the reaction, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 5:1) to give the product, N-methyl-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63%) as a brown solid. 1H NMR(400MHz,CDCl3)δ 8.10(s,1H),6.14(s,1H),3.01(d,J=4.8Hz,3H),0.29(s,9H). 13 C NMR (101 MHz, 155-156 °C).

[0072] 12811481 To N-methyl-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (0.21 mmol), K2CO3 (58 mg, 0.42 mmol) in 3 mL of THF was added 1 mL of MeOH at 0 °C, and the reaction was stirred for 30 min at 0 °C. After completion of the reaction, the mixture was filtered, washed with THF, and the filtrate was concentrated at low temperature to give the desired product as a brown solid (55 mg, 98%). 1 H NMR(400MHz,CDCl3)δ 8.11(s,1H),6.25(s,1H),3.57(s,1H),3.01(d,J=4.9Hz,3H). 13 C NMR(101MHz,CDCl3)δ 160.22,150.49,142.97,136.16,84.05,75.97,26.90.ESIMS m / z 167([M+H]+).Mp,118-119 °C.

[0073] 12811473 To N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol) in 3 mL of THF was added 1 mL of MeOH at 0° C., and the reaction was stirred for 30 minutes at 0° C. After completion of the reaction, the mixture was filtered, washed with THF, and the filtrate was concentrated at low temperature to give the product as a brown solid (40 mg, 86%).

[0074] 12811475 To N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol) in 3 mL of THF was added 1 mL of MeOH at 0° C., and the reaction was stirred for 30 minutes at 0° C. After completion of the reaction, the mixture was filtered, washed with THF, and the filtrate was concentrated at low temperature to give the product as a brown solid (40 mg, 86%).

[0075] 12811477 To N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol) in 3 mL of THF was added 1 mL of MeOH at 0° C., and the reaction was stirred for 30 minutes at 0° C. After completion of the reaction, the mixture was filtered, washed with THF, and the filtrate was concentrated at low temperature to give the product as a brown solid (40 mg, 86%). 1 H NMR(400MHz,CDCl3)δ 8.09(s,1H),5.70(s,1H),4.01-3.92(m,1H),3.56(s,1H),1.70-1.61(m,2H),1.54-1.45(m,2H),0.95(t,J=7.4Hz,6H). 13 C NMR(101MHz,CDCl3)δ 159.30,150.41,142.57,136.71,83.90,76.03,67.98,53.11,27.48,10.29.ESIMS m / z 223([M+H]+).Mp,81-82 °C.

[0076] 12811479 To a solution of trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), and NEt3 (1.5 mL) in 4.5 mL of THF under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidophenyl)benzamide (150 mg, 0.54 mmol) was added. The reaction was stirred at 50 °C for 2 h. After completion of the reaction, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 5:1) to give product 1 (161 mg, 64%) as a brown solid.

[0077] 12811481 To a solution of trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), and NEt3 (1.5 mL) in 4.5 mL of THF under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidophenyl)benzamide (150 mg, 0.54 mmol) was added. The reaction was stirred at 50 °C for 2 h. After completion of the reaction, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 5:1) to give product 1 (114 mg, 72%) as a brown solid.

[0078] 12811485 To a solution of trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), and NEt3 (1.5 mL) in 4.5 mL of THF under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidophenyl)benzamide (150 mg, 0.54 mmol) was added. The reaction was stirred at 50 °C for 2 h. After completion of the reaction, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 5:1) to give product 1 (150 mg, 49%) as a white solid.

[0079] 12776911 To a solution of ethyl 2-bromooxazole-4-carboxylate La (1.5 g, 6.81 mmol) in toluene (10 mL) under an argon atmosphere was added CuI (0.13 g, 0.0.68 mmol), DIPEA (1.75 g, 13.62 mmol), PdCl(PPh) (0.24 g, 0.34 mmol), and trimethylsilylacetylene (1 g, 10.21 mmol), and the reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was cooled to RT, EtOAc (150 mL) was added, and the mixture was filtered through a Celite pad. The filtrate was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh) eluting with 5-10% EtOAc in petroleum ether to give 0.8 g (50%) of the desired product, a brown liquid; FT-IR 1737.89 cm -1 (C=O stretch present); 1 H NMR(400MHz,CDCl3)δ 8.16(s,3H),4.39(q,J=7.2Hz,2H),1.38(t,J=7.2Hz,3H),0.27(s,9H);ESIMS m / z 238.22([M+H]+).

[0080] 12776913 To a solution of 2-ethynyloxazole-4-carboxylic acid (0.8 g, 3.37 mmol) in a 3:1 THF-HO mixture (10 mL) was added LiOH·HO (0.14 g, 3.37 mmol), and the reaction mixture was stirred at RT for 2 h. The reaction mixture was acidified with 1 N HCl and extracted with DCM. The organic layer was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 0.6 g (86%) of the desired product as a brown solid; melting point 161–165 °C. 1 H NMR(400MHz,DMSO-d6)δ 13.35(bs,1H),8.83(s,1H),4.95(s,1H);ESIMS m / z 138.16([M+H]+).

[0081] 12776915 To a solution of 2-ethynyloxazole-4-carboxylic acid (0.1 g, 0.72 mmol) and amine input (0.073 g, 0.87 mmol) in DMF (3 mL) was added HATU (0.42 g, 1.09 mmol) and DIPEA (0.19 g, 1.44 mmol) at 0 °C, and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc. The organic layer was washed with ice water, brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh) eluting with 30-35% EtOAc in petroleum ether to give 0.08 g (54%) of the desired brown solid.

[0082] 12776921 To a solution of 2-ethynyloxazole-5-carboxylic acid (0.35 g, 2.55 mmol) and the amine input (0.318 g, 3.83 mmol) in DMF (5 mL) was added HATU (1.45 g, 3.82 mmol) and DIPEA (0.98 g, 7.66 mmol) at 0 °C, and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc. The organic layer was washed with ice water, brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh) eluting with 20-25% EtOAc in petroleum ether to give the product as an off-white solid (0.240 g, 46%); melting point: 133-137 °C. 1 H NMR(400MHz,CDCl3)δ 7.70(s,1H),6.30(s,1H),3.33(s,1H),2.41(s,1H),1.75(s,6H);ESIMS m / z 203.13([M+H]+).

[0083] 12776925 To a solution of ethyl 2-iodooxazole-5-carboxylate h1 (2.5 g, 9.36 mmol) in toluene (25 mL) under an argon atmosphere, CuI (0.178 g, 0.93 mmol), DIPEA (2.4 g, 18.72 mmol), PdCl2(PPh3)2 (0.33 g, 0.468 mmol), and trimethylsilylacetylene (1.8 g, 18.72 mmol) were added, and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled to RT. EtOAc (100 mL) was added, filtered through a Celite pad, and the filtrate was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh) eluting with 5-10% EtOAc in petroleum ether to give the product, 1 g (45%), brown liquid; FT-IR 1733.07 cm -1 (C=O stretch present); 1H NMR(400MHz,CDCl3)δ 7.73(s,1H),4.39(q,J=7.2Hz,2H),1.38(t,J=7.2Hz,3H),0.28(s,9H);ESIMS m / z 238.15([M+H]+).

[0084] 12791853 To a solution of 2-ethynyloxazole-4-carboxamide (0.3 g, 2.18 mmol) in THF (5 mL) and aqueous NH3 (2 mL) was added HATU (1 g, 2.62 mmol) and DIPEA (0.42 g, 3.28 mmol) at 0 °C, and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc. The organic layer was washed with ice water, brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh) eluting with 40-45% EtOAc in petroleum ether to give the product as a light brown solid (0.05 g, 42%); melting point 176-180 °C; 1 H NMR(400MHz,DMSO-d6)δ 8.65(s,1H),7.79(s,1H),7.58(s,1H),4.95(s,1H);ESIMS m / z 137.12([M+H]+).

[0085] 12797705 To a stirred solution of 2-((trimethylsilyl)ethynyl)oxazole-4-carbaldehyde (0.2 g, 0.80 mmol) in MeOH (2 mL) was added K2CO3 (1 mg, catalytic amount) at RT. The reaction mixture was stirred at RT for 5 min. After completion of the reaction, the reaction mixture was poured into ice water (5 mL), acidified with 1 N HCl (2 mL, pH 4), and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using an eluent of 10% EtOAc in petroleum ether to give the product as an off-white solid (0.078 g, 43%); melting point: 110-114 °C. 1H NMR(400MHz,CDCl3)δ 9.93(s,1H),8.24(s,1H),3.33(s,1H);ESIMS m / z 122.12([M+H]+).

[0086] 12806755 To a stirred solution of 1-(2-((trimethylsilyl)ethynyl)oxazol-4-yl)prop-2-yn-1-ol (0.27 g, 1.14 mmol) in dichloromethane (6 mL) was added DMP (0.63 g, 1.49 mmol) at 0°C. The reaction mixture was stirred at RT for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 24 g) using an eluent of 10% EtOAc in petroleum ether to give the product as a light brown solid (0.12 g, 42%); melting point 75-79°C; 1 H NMR(400MHz,CDCl3)δ 8.29(s,1H),3.44(s,1H),0.29(s,9H);ESIMS m / z 218.15([M+H]+).

[0087] 12806763 To a stirred solution of 1-(2-((trimethylsilyl)ethynyl)oxazol-4-yl)prop-2-yn-1-one (0.2 g, 0.80 mmol) in MeOH (2 mL) was added K2CO3 (1 mg, catalytic amount) at RT. The reaction mixture was stirred at RT for 5 min. After completion of the reaction, the reaction mixture was poured into ice water (5 mL), acidified with 1 N HCl (2 mL, pH 4), and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using an eluent of 10% EtOAc in petroleum ether to give a light brown solid (0.024 g, 45%); melting point: 117-121 °C. 1 H NMR(400MHz,CDCl3)δ 8.32(s,1H),3.45(s,1H),3.33(s,1H);ESIMS m / z 146.05([M+H]+).

[0088] 12811459 To N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol) in 3 mL of THF was added 1 mL of MeOH at 0° C., and the reaction was stirred for 30 minutes at 0° C. After completion of the reaction, the mixture was filtered, washed with THF, and the filtrate was concentrated at low temperature to give the product as a yellow solid (25 mg, 86%).

[0089] 12811483 To N-(pentan-3-yl)-2-((trimethylsilyl)ethynyl)thiazole-5-carboxamide (63 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol) in 3 mL of THF was added 1 mL of MeOH at 0 °C, and the reaction was stirred for 30 min at 0 °C. After completion of the reaction, the mixture was filtered, washed with THF, and the filtrate was concentrated at low temperature to give the product as a brown solid (85%). 1 H NMR(400MHz,CDCl3)δ 7.75(s,1H),6.45(s,1H),4.24(dd,J=5.4,2.6Hz,2H),3.35(s,1H),2.31(t,J=2.6Hz,1H). 13 C NMR(101MHz,CDCl3)δ 155.57,145.61,145.06,132.07,81.61,78.37,72.49,70.68,29.09.ESIMS m / z 175([M+H]+).Mp,112-113 °C.

[0090] 12811491 To trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), and NEt3 (1.5 mL) in 4.5 mL of THF under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidophenyl)benzamide (150 mg, 0.54 mmol) was added. The reaction was stirred at 50 °C for 2 h. After completion of the reaction, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 5:1) to give the product as a yellow oil.

[0091] 12811493 To trimethylsilylacetylene (317 mg, 3.23 mmol), Pd(PPh3)4 (62 mg, 0.05 mmol), Cul (21 mg, 0.11 mmol), and NEt3 (1.5 mL) in 4.5 mL of THF under N2, 2-bromo-N-(pentan-3-yl)thiazole-5-carboxamidophenyl)benzamide (150 mg, 0.54 mmol) was added. The reaction was stirred at 50 °C for 2 h. After completion of the reaction, the mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 5:1) to give the product as a white solid (25%). 1 H NMR(400MHz,CDCl3)δ 7.73(s,1H),6.45(s,1H),4.23(dd,J=5.4,2.6Hz,2H),2.30(t,J=2.5Hz,1H),0.30(s,9H). 13 C NMR(101MHz,CDCl3)δ 156.53,147.07,145.37,132.91,102.42,91.08,79.24,73.24,29.85.ESIMS m / z 247([M+H]+).Mp,134-135 °C.

[0092] 12771961 To a solution of N-(2-methylbut-3-yn-2-yl)-2-(trichloromethyl)-4-(trifluoromethyl)thiazole-5-carboxamide (273 mg, 0.719 mmol) in THF:HO (5:1, 6 mL) was added Fe(s) in one portion. The resulting reaction mixture was warmed to 60 °C. The temperature was maintained for 16 h (starting at 4 pm). The reaction was followed by TLC (n-hexane:ethyl acetate 8:2) and LCMS. After 16 h, no SM was observed by TLC. The reaction mixture was concentrated (nitrogen), adsorbed onto a Celite precolumn, and chromatographed on silica gel.

[0093] 12799175 To a solution of 5-ethynylthiazole-2-carbaldehyde (40 mg, 0.292 mmol) in anhydrous THF at −78 °C was slowly added methylmagnesium bromide (86 μL, 0.292 mmol) as a 3.4 molar solution in THF. After the addition was complete, the reaction was allowed to warm slowly to 25 °C over 30 min, then quenched with saturated aqueous NH4Cl and diluted with 50 mL of ether. The layers were partitioned, and the ether layer was dried over magnesium sulfate and concentrated with a stream of nitrogen to give a brown residue (42 mg, 85%).

[0094] 12816775 To a stirred solution of (5-ethynylfuran-2-yl)methanol (0.1 g, 0.82 mmol) in THF (5 mL) was added NaH (60%, 0.078 g, 1.63 mmol) and CHCl (0.12 mL, 2.04 mmol) at 0 °C. The reaction mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using 5-10% EtOAc in petroleum ether to give the product as a light brown liquid (0.026 g, 23%); FT IR 2111.13 cm -1 (C≡C stretching exists); 1H NMR(400MHz,CDCl3)δ 6.60(d,J=3.2Hz,1H),6.31(d,J=3.6Hz,1H),4.37(s,2H),3.38(s,3H),3.37(s,1H);ESIMS m / z 135.9([M]+).

[0095] 12816797 To a stirred solution of 1-(5-ethynylfuran-2-yl)ethan-1-ol (0.1 g, 0.60 mmol) in DMF (5 mL) was added K2CO3 (0.1 g, 0.73 mmol) and methyl iodide (0.1 mL, 1.20 mmol) at RT. The reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using 10-20% EtOAc in petroleum ether to give the product as a brown liquid (0.026 g, 26%); FT IR 3288.69 cm -1 (OH stretching present); 1 H NMR(400MHz,CDCl3)δ 6.59(d,J=3.6Hz,1H),6.22(dd,J=0.4,3.2Hz,1H),4.86(q,J=4.4Hz,1H),3.39(s,1H),1.92(d,J=4.4Hz,1H),1.54(d,J=6.8Hz,3H);ESIMS m / z 135.9([M]+).

[0096] 12830209 To a stirred solution of 1-(2-ethynyloxazol-4-yl)ethan-1-ol (0.1 g, 0.72 mmol) in THF (5 mL) was added NaH (48 mg, 0.72 mmol) at 0 °C and stirred for 15 min at 0 °C, followed by the addition of CHCl (0.091 mL, 1.45 mmol). The reaction mixture was slowly warmed to RT and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with cold water (10 mL) and extracted with EtOAc. The combined organic layers were dried over NaSO and concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 24 g) using an eluent of 10–20% EtOAc in petroleum ether to give product-A8 (0.036 g, 33%) as a pale yellow liquid; FT IR 2121.70 cm -1 (C≡C stretching exists); 1 H NMR(400MHz,CDCl3)δ 7.54(s,1H),4.36(q,J=6.0Hz,1H),3.36(s,3H),3.23(s,1H),1.48(d,J=6.4Hz,3H); 13 C NMR(101MHz,CDCl3)δ 145.58,143.86,135.94,79.91,72.18,71.29,56.66,20.13;ESIMS m / z 152.07([M+H]+).

[0097] 12830213 To a stirred solution of 1-(2-((trimethylsilyl)ethynyl)oxazol-4-yl)ethan-1-one (0.3 g, 1.55 mmol) in THF (10 mL) was added CHMgI [3 M in diethyl ether (0.6 mL, 1.86 mmol)] at 0 °C. The reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NHCl (20 mL) and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 24 g) using an eluent of 10–20% EtOAc in petroleum ether to give Int-A-1-5 (0.2 g, 59%) as a pale yellow liquid; FT IR 2175.70 cm-1 (C≡C stretching exists); 1 H NMR(400MHz,CDCl3)δ 7.49(s,1H),4.83(q,J=6.8Hz,1H),2.15(d,J=4.8Hz,1H),1.52(d,J=6.4Hz,3H),0.27(d,9H);ESIMS m / z 210.18([M+H]+).

[0098] 12853673 To a stirred solution of thiazole-2-thiol (0.3 g, 2.56 mmol) in acetone (10 mL) was added K2CO3 (0.35 g, 2.56 mmol) and propargyl bromide (0.2 mL, 2.56 mmol) at 0 °C. The reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the product as a brown liquid (0.15 g, 38%); FT IR 2117.84 cm -1 (C≡C stretching exists); 1 H NMR(400MHz,CDCl3)δ 7.73(d,J=3.2Hz,1H),7.28(d,J=3.2Hz,1H),3.95(d,J=2.8Hz,2H),2.28(t,J=5.2Hz,1H);ESIMS m / z 156.12([M+H]+).

[0099] 12853681 To a stirred solution of 2-bromothiazole (0.3 g, 1.82 mmol) in 1,4-dioxane (10 mL) was added LiCl (0.23 g, 5.48 mmol) and CuI (0.1 g, 0.55 mmol) at RT. The reaction mixture was degassed with argon for 5 min, and then Input-1 (0.66 g, 2.01 mmol) and Pd(PPh3)4 (0.1 g, 0.09 mmol) were added at RT. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using 5–10% EtOAc in petroleum ether to give the product as a brown liquid (0.05 g, 22%); FT IR 2235.50 cm -1 (C≡C stretching exists); 1 H NMR(400MHz,DMSO-d6)δ 7.84(d,J=3.2Hz,1H),7.77(d,J=3.6Hz,1H),2.14(s,3H);ESIMS m / z 123.92([M+H]+).

[0100] 12853683 To a stirred solution of 2-bromothiazole (1 g, 6.09 mmol) in EtOAc (20 mL) was added EtN (3.6 mL, 26.21 mmol) and CuI (12 mg, 0.06 mmol) at RT. The reaction mixture was degassed with argon for 5 min, and then prop-2-yn-1-ol (Input-2) (1.6 mL, 29.26 mmol) and bis(triphenylphosphine)palladium chloride (0.2 g, 0.30 mmol) were added at RT. The reaction mixture was stirred at 50-55 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using 10-15% EtOAc in petroleum ether to give the product (0.25 g, 29%) as a brown liquid; FT IR 2231.64 cm -1 (C≡C stretching exists); 1H NMR(400MHz,DMSO-d6)δ 7.91(d,J=3.6Hz,1H),7.86(d,J=3.2Hz,1H),5.53(t,J=6.2Hz,1H),4.36(d,J=6.0Hz,2H);ESIMS m / z 139.94([M+H]+).

[0101] 12853685 To a stirred solution of 2-bromothiazole (1 g, 6.09 mmol) in EtOAc (20 mL) was added EtN (3.6 mL, 26.21 mmol) and CuI (12 mg, 0.06 mmol) at RT. The reaction mixture was degassed with argon for 5 min, and then alkyne (1.6 mL, 29.26 mmol) and bis(triphenylphosphine)palladium chloride (0.2 g, 0.30 mmol) were added at RT. The reaction mixture was stirred at 50-55 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using 10%-15% EtOAc in petroleum ether to give the desired product as a brown liquid (0.4 g, 43%); FT IR 2231.64 cm -1 (C≡C stretching exists); 1 H NMR(400MHz,DMSO-d6)δ 7.84(d,J=3.2Hz,1H),7.78(d,J=3.2Hz,1H),4.99(t,J=5.6Hz,1H),3.60(q,J=5.6Hz,2H),2.64(t,J=6.6Hz,2H);ESIMS m / z 153.95([M+H]+).

[0102] 12853687 To a stirred solution of 2-bromothiazole (1 g, 6.09 mmol) in EtOAc (20 mL) was added EtN (3.6 mL, 26.21 mmol) and CuI (12 mg, 0.06 mmol) at RT. The reaction mixture was degassed with argon for 5 min, and then prop-2-yn-1-ol (Input-2) (1.6 mL, 29.26 mmol) and bis(triphenylphosphine)palladium chloride (0.2 g, 0.30 mmol) were added at RT. The reaction mixture was stirred at 50-55 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using 10% to 15% EtOAc in petroleum ether to give the product, a brown liquid (0.1 g, 21%); FT IR 2231.64 cm -1 (C≡C stretching exists); 1 H NMR(400MHz,CDCl3)δ 7.83(d,J=3.2Hz,1H),7.36(d,J=3.6Hz,1H),4.37(s,2H),3.47(s,3H);ESIMS m / z 153.1([M]+).

[0103] 12855341 To a stirred solution of 2-bromothiazole (0.3 g, 2.56 mmol) in acetone (10 mL) was added K2CO3 (0.35 g, 2.56 mmol) and propargyl alcohol (0.2 mL, 2.56 mmol) at 0 °C. The reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a colorless liquid (0.03 g, 17%); FT IR 2239.36 cm -1 (C≡C stretching exists); 1 H NMR(400MHz,CDCl3)δ 7.13(d,J=3.6Hz,1H),6.70(d,J=4.0Hz,1H),5.00(q,J=2.4Hz,2H),1.89(t,J=2.2Hz,3H);ESIMS m / z 153.83([M+H]+).

[0104] 12855343 To a stirred solution of 2,4-dibromothiazole (0.5 g, 2.07 mmol) in 1,4-dioxane (10 mL) was added CsF (0.47 g, 3.11 mmol) at RT. The reaction mixture was degassed with argon for 5 minutes, and then Input-1 (0.82 g, 2.48 mmol) and Pd(tBuP) (53 mg, 0.11 mmol) were added at RT. The reaction mixture was stirred at 100 °C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using 5% to 10% EtOAc in petroleum ether to give the product (0.2 g, 41%) as a yellow semi-solid (0.15 g, 45%); FT IR 2235.50 cm -1 (C≡C stretching exists) 1 H NMR(400MHz,CDCl3)δ 7.22(s,1H),2.10(s,3H),2.04(s,3H);ESIMS m / z 161.88([M+H]+).

[0105] 12856621 3-Ethynyl-5-methylisothiazole (1.0 equiv.) was dissolved in anhydrous methanol (0.2–0.5 mM), charged with cesium carbonate (1.0 equiv.), and cooled to 0–5° C. Dimethyl (l-diazo-2-oxopropyl)phosphonate (1.0 equiv.) was added dropwise, and the reaction was then stirred for 1–18 h, after which the crude mixture was concentrated onto silica gel and directly purified by flash silica gel chromatography to afford the desired alkyne.

[0106] 12858893 To a stirred solution of TMS acetylene (0.9 mL, 8.01 mmol) in THF (15 mL) was added n-BuLi (2.5 M) (3.2 mL, 7.69 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 30 min. Then, furan-2-carbaldehyde SM-C (0.5 g, 6.41 mmol) was added to the reaction mixture at -78 °C and stirred at RT for 5 h. After completion of the reaction, the reaction mixture was quenched with aqueous NH4Cl (10 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 40 g) using an eluent of 15% to 20% EtOAc in petroleum ether to give Int-C1 (0.2 g, 16%) as a yellow solid; FT IR 2177.63 cm -1 (C≡C stretching exists); 1 H NMR(400MHz,CDCl3)δ 7.41(m,1H),6.45(m,1H),6.35(m,1H),5.45(d,J=6.8Hz,1H),2.22(d,J=7.2Hz,1H),0.21(s,9H);ESIMS m / z 194.94([M+H]+).

[0107] Synthesis of 1-(furan-2-yl)-3-(trimethylsilyl)prop-2-yn-1-one: To a stirred solution of 1-(furan-2-yl)-3-(trimethylsilyl)prop-2-yn-1-ol (0.1 g, 0.51 mmol) in DCM (5 mL) was added pyridinium chlorochromate (0.16 g, 0.77 mmol) at RT. The reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 24 g) using 2% to 5% EtOAc in petroleum ether to give the product (0.03 g, 30%) as a brown liquid; FT IR 2158.35 cm -1 (C≡C stretching exists); 1H NMR(400MHz,CDCl3)δ 7.66(m,1H),7.36(m,1H),6.57(dd,J=1.6,3.6Hz,1H),0.29(s,9H);ESIMS m / z 192.90([M+H]+).

[0108] Basic Procedure A In air, an aryl halide (1 equiv.), triethylamine (3 equiv.), and copper(I) iodide (0.1 equiv.) were placed in a 20 mL vial and diluted with dioxane (substrate concentration 0.3 M). The reaction was degassed for 5 minutes, and then ethynyltrimethylsilane (4.0 equiv.) and bis(triphenylphosphine)palladium(II) chloride (0.1 equiv.) were added under an inert atmosphere. The vial was placed in a heating block heated to 80 °C, and the solution was stirred for 20 hours. The reaction was cooled and passed through a pad of Celite. The filtrate was concentrated, and the resulting residue was purified by flash chromatography on silica gel.

[0109] Basic Procedure B To a 50 mL RBF containing TMS-alkyne (1.0 equiv.) was added MeOH (substrate concentration 0.25 M) and potassium carbonate (0.2 equiv.). The reaction was stirred at ambient temperature for 30 minutes. After completion, the reaction was diluted with HO and extracted with DCM. The combined organic phases were passed through a phase separator and concentrated. The resulting residue was purified by flash chromatography on silica gel.

[0110] Basic Procedure C The aldehyde (1.0 equiv.) was dissolved in anhydrous methanol (0.2–0.5 mM), charged with cesium carbonate (1.0 equiv.), and cooled to 0–5° C. Dimethyl (l-diazo-2-oxopropyl)phosphonate (1.0 equiv.) was added dropwise, after which the reaction was stirred for 1–18 h, after which the crude mixture was concentrated onto silica gel and directly purified by flash silica gel chromatography to afford the desired alkyne.

[0111] Basic Procedure D A 20 mL vial was charged with sodium hydride (60% by weight, 1.0 equiv.) and diluted with THF (1.0 M substrate concentration) under an inert atmosphere. Alcohol (1.0 equiv.) was then added at ambient temperature, and the reaction was stirred for 30 minutes. An aryl halide (1.0 equiv.) in THF (0.5 M substrate concentration) was then added. The vial was placed in a heating block heated to 50 °C, and the solution was stirred for 20 hours. The reaction was quenched with saturated NH4Cl and extracted with Et2O. The combined organics were dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel.

[0112] Basic Procedure E In air, a 20 mL vial equipped with a magnetic stir bar was charged with P(tBu)PdG2 (0.03 equiv.) and an aryl halide (1 equiv. if solid). The vial was capped and purged by evacuating and refilling with nitrogen three times. Dry DMF (substrate concentration 0.4 M) was added to the vial, followed by the aryl halide (1 equiv. if liquid), TMS-protected alkyne (1.5 equiv.), and TBAF (1.5 equiv., 1 M in THF). The vial was placed in a heating block heated to 80 °C, and the solution was stirred for 20 h. After the reaction time, the vial was opened to the atmosphere, and aqueous Na2CO3 (4 mL) was added. The crude product was extracted with CHCl2 and purified by flash chromatography on silica gel.

[0113] Basic Procedure F A 20 mL vial was charged with sodium alkoxide (1.0 equiv.). A solution of aryl halide (1.0 equiv.) in THF (substrate concentration 0.2 M) was then added. The vial was placed in a heating block heated to 50 °C, and the solution was stirred for 20 h. The reaction was quenched with saturated NH4Cl and extracted with Et2O. The combined organics were dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel.

[0114] Basic Procedure G A stock solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.1 equiv.) in dioxane (2 mL), copper(I) iodide (0.1 equiv.) in dioxane (1 mL), and triethylamine (3 equiv.) were added to a vial containing a solution of Br / Cl-heterocycle (1 equiv.) in dioxane (2 mL). The contents were sealed and degassed with nitrogen. The overall reaction concentration was 0.2 M. With stirring, neat ethynyltrimethylsilane (2 equiv.) was added, and the contents were heated to 60 °C overnight for 18 h. The reaction was quenched with AcOH (10 equiv.), and the mass of the product was monitored by LCMS. The contents were diluted with EtOAc and partitioned between 2.5 M KHCO3 (2x) and brine, then dried over MgSO4. The contents were concentrated by rotary evaporation and the residue was purified by silica gel chromatography eluting with 10-100% hexanes / EtOAc over 10 minutes to give the product.

[0115] Basic Procedure H A solution of potassium fluoride (0.1 M, 2 equiv.) in methanol was dissolved in the flask containing the ((trimethylsilyl)ethynyl)-heterocycle and stirred at ambient temperature for 18 h. The contents were concentrated by rotary evaporation and purified on silica gel eluting with 0-10% DCM / MeOH to give the product.

[0116] Basic Step I To a stirring solution of the aldehyde (1 M, 1 equiv.) and potassium carbonate (2 equiv.) in methanol was added neat dimethyl (1-diazo-2-oxopropyl)phosphonate (1.1 equiv.). Gas evolution was observed. The contents were stirred at ambient temperature for 2-5 h. The contents were diluted with water and extracted with dichloromethane. The combined organics were dried over MgSO4 and concentrated by fractional distillation. The residue was purified on a silica gel column eluting with 0-10% DCM / MeOH over 10 min. The product-containing fractions were collected and evaporated to give the product.

[0117] Procedure J Nitrogen-containing heterocycles bearing alkynes were dissolved in diethyl ether (1 M) and treated with an equal volume of 1 M acid (HCl or anhydrous H3PO4) in diethyl ether. Volatile components were removed by evaporation using a stream of nitrogen gas to give the desired heterocycles in salt form.

[0118] Basic Procedure K To a stirred solution of 2-bromothiazole (1 g, 6.09 mmol) in EtOAc (20 mL) was added EtN (3.6 mL, 26.21 mmol) and CuI (12 mg, 0.06 mmol) at RT. The reaction mixture was degassed with argon for 5 min, and then prop-2-yn-1-ol (1.6 mL, 29.26 mmol) and bis(triphenylphosphine)palladium chloride (0.2 g, 0.30 mmol) were added at RT. The reaction mixture was stirred at 50–55 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 12 g) using 10%–15% EtOAc in petroleum ether to give the desired product.

[0119] Basic procedure L To a stirred solution of alkynyl alcohol (0.15 g, 1.07 mmol) in dichloromethane (10 mL) was added EtN (0.2 mL, 1.60 mmol) and acetyl chloride (0.1 mL, 1.28 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, poured into water, and extracted with DCM. The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by flash column chromatography (column size: 24 g) using 10% to 15% EtOAc in petroleum ether to give the desired product.

[0120] Basic Procedure M To a stirred solution of thiazole-2-thiol (0.3 g, 2.56 mmol) in acetone (10 mL) was added K2CO3 (0.35 g, 2.56 mmol) and methyl propargyl bromide (0.2 mL, 2.56 mmol) at 0 °C. The reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product.

[0121] Basic Procedure N To a stirred solution of 3-bromopyrazole (0.5 g) in TEA (5 mL) was added CuI (0.049 g). The reaction mixture was then degassed with argon gas for 10 minutes, followed by the addition of Pd(PPh3)4 (0.148 g) and acetylated alkyne input (5.14 mmol) at room temperature. The resulting reaction mixture was stirred at 80 °C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at 38 °C to give the crude compound, which was purified by preparative HPLC to give the desired product.

[0122] Basic Procedure To a stirred solution of pyrazole (0.5 g) in dry THF (5 V) was added NaH (2 equiv.) followed by propargyl bromide (1.2 equiv.) at 0 °C. The resulting reaction mixture was stirred from 0 °C to RT for 3 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water, extracted with ethyl acetate, washed with aqueous NaCl, and dried over anhydrous NaSO. The resulting solution was concentrated under reduced pressure at 38 °C to give the crude compound, which was purified by Combiflash chromatography to give the desired product.

[0123] Analysis method The synthesized compounds were characterized by the following methods: melting point, ESIMS-electrospray mass spectrometry, HRMS-high resolution mass spectrometry, EIMS-electron ionization mass spectrometry, GCMS-gas chromatography mass spectrometry, SIMS-secondary ion mass spectrometry, Fourier transform infrared spectroscopy-FTIR, 1 H, 13 C.19 F, and 31 P nuclear magnetic resonance spectroscopy.

[0124] Chiral structures in Table 1 are indicated with an "&1" adjacent to the chiral center.

[0125] [Table 1]

[0126] [Table 2]

[0127] [Table 3]

[0128] [Table 4]

[0129] [Table 5]

[0130] [Table 6]

[0131] [Table 7]

[0132] [Table 8]

[0133] [Table 9]

[0134]

Table 10

[0135]

Table 11

[0136]

Table 12

[0137]

Table 13

[0138]

Table 14

[0139]

Table 15

[0140] Table 16

[0141]

Table 17

[0142]

Table 18

[0143]

Table 19

[0144] Table 20

[0145] Table 21

[0146] Table 22

[0147] Table 23

[0148] Table 24

[0149] Table 25

[0150] Table 26

[0151] Table 27

[0152] Table 28

[0153] Table 29

[0154] Table 30

[0155] Table 31

[0156] Table 32

[0157] Table 33

[0158] Table 34

[0159] Table 35

[0160] Table 36

[0161] Table 37

[0162] Table 38

[0163] Table 39

[0164] Table 40

[0165] Table 41

[0166] Table 42

[0167] Table 43

[0168] Table 44

[0169] Table 45

[0170] Table 46

[0171] Table 47

[0172] Table 48

[0173] Table 49

[0174]

Table 50

[0175] Table 51

[0176] Table 52

[0177] Table 53

[0178] Table 54

[0179] Table 55

[0180] Table 56

[0181] Table 57

[0182] Table 58

[0183] Table 59

[0184] Table 60

[0185] Table 61

[0186] Table 62

[0187] Table 63

[0188] Table 64

[0189] Table 65

[0190] Table 66

[0191] Table 67

[0192] Table 68

[0193] Table 69

[0194] Table 70

[0195] Table 71

[0196] Table 72

[0197] Table 73

[0198] Table 74

[0199] Table 75

[0200] Table 76

[0201] Table 77

[0202] Table 78

[0203] Table 79

[0204] Table 80

[0205] Table 81

[0206] Table 82

[0207] [Table 83]

[0208] [Table 84]

[0209] [Table 85]

[0210] [Table 86]

[0211] [Table 87]

[0212] [Table 88]

[0213] [Table 89]

[0214] [Table 90]

[0215] Biological Testing Compound preparation: Compounds were dissolved in DMSO at a concentration of 0.1 mM.

[0216] Soil Slurry Preparation: Two different soils were sourced from Kalamazoo, Michigan (loamy fine sand) and Windfall, Indiana (clay loam). After collection, the soils were sieved to 2 mm and stored at 4°C for no longer than 6 months. The slurry was prepared by weighing 143 grams of wet field soil per liter of nitrification medium containing chlorate blocks (0.8 μm KHPO, 0.1 μm KHPO, 0.5 μm (NH)SO, 10 μm NaClO) into a Pyrex dish and stirring for 5 minutes.

[0217] Experimental Procedure: While stirring, 900 μL of the slurry was pipetted into a 96-deep-well plate. After slurry addition, 9 μL of a 0.1 mM stock solution of compound or solvent control (i.e., DMSO) was immediately added to the designated well for a final concentration of 0.1 μM. A sealing mat was placed on top of the plate, and the plate was mixed by inverting it three times. The plate was incubated at 28°C for 48 hours with side-to-side shaking at 225 rpm. After 48 hours, the plate was centrifuged at 3,000 rpm for 15 minutes, and the supernatant was analyzed for nitrite concentration using a colorimetric Griess assay. Nitrification rates were determined by the total amount of nitrite formed during the incubation period. Nitrification inhibition was determined by normalizing the nitrification rate to the DMSO control. Relative inhibition of the tested compounds was further normalized to the reference nitrification inhibitor, nitrapyrin.

[0218] The results are shown in Table 3.

[0219] [Table 91]

[0220] [Table 92]

[0221] [Table 93]

[0222] Table 94

[0223] Table 95

[0224] Table 96

[0225] Table 97

Claims

1. Carrier and A nitrification inhibitory composition containing a compound selected from the group consisting of the following: 【Chemistry 1】 (In these formulas, R ２ , １ ~R ４ is independently H, ethynyl, trimethylsilyl-ethynyl, C １ ~C ６ alkoxy, C １ ~C ６ thioalkyl, C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, C １ ~C ６ alkenyl, C ３ ~C ６ cycloalkenyl, C １ ~C ６ haloalkyl, C １ ~C ６ haloalkenyl, C １ ~C ６ haloalkyl, C​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​, C(=O)Et, C(=O)C=CCH ３ , C(=O) C≡C, C(=O)N(CH ３ )CH ３ And R １ ~R ４ (At least one of them is C≡C or C≡C-TMS); 【Chemistry 2】 (wherein, R １１ ~R １４ are independently H, ethynyl, trimethylsilyl-ethynyl, C １ ~C ６ alkoxy, C １ ~C ６ thioalkyl, C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, C １ ~C ６ alkenyl, C ３ ~C ６ cycloalkenyl, C １ ~C ６ haloalkyl, C １ ~C ６ haloalkenyl, C １ ~C ６ haloalkyl, C １ ~C ６ haloalkoxy, benzyl, CH(OH)CH ３ , C(=O)NH ２ , CO​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ ３ , C(=O) C≡C, C(=O)N(CH ３ ), CH ３ where, R １１ to R １４ at least one of which is C≡C or C≡C-TMS); 【Transformation 3】 (In the formula, R ２１ ~R ２４ These are independently H, ethynyl, trimethylsilyl-ethynyl, and C １ ~C ６ Alkoxy, C １ ~C ６ Thioalkyl, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkenil, C ３ ~C ６ Cycloalkenyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkenil, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, benzyl, CH(OH)CH ３ , C(=O)NH ２ CO ２ H, CO ２ Me, CO ２ Et, C(=O)H, CH ２ OH, halogen, C(=O)NHCH ２ C≡C, C(=O)NHCH(CH ３ )C≡C, C(=O)NHCH(CH ２ CH ３ )C≡C, C≡N, C(=O)NHC(CH ３ ) (CH ３ )C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH ３ )CH ３ , C(=O)NHCH(CH ３ )CH ２ CH ３ , C(=O)NHCH(CH ２ CH ３ )CH ２ CH ３ C(=O)alkyl, C(=O)haloalkyl, C(=O)CH ３ , C(=O)Et, C(=O)C=CCH ３ , C(=O) C≡C, C(=O)N(CH ３ )CH ３ And R ２１ ~R ２４ (At least one of them is C≡C or C≡C-TMS); 【Chemistry 4】 (In the formula, R ３１ ~R ３４ These are independently H, ethynyl, trimethylsilyl-ethynyl, and C １ ~C ６ Alkoxy, C １ ~C ６ Thioalkyl, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkenil, C ３ ~C ６ Cycloalkenyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkenil, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, benzyl, CH(OH)CH ３ , C(=O)NH ２ CO ２ H, CO ２ Me, CO ２ Et, C(=O)H, CH ２ OH, halogen, C(=O)NHCH ２ C≡C, C(=O)NHCH(CH ３ )C≡C, C(=O)NHCH(CH ２ CH ３ )C≡C, C≡N, C(=O)NHC(CH ３ ) (CH ３ )C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH ３ )CH ３ , C(=O)NHCH(CH ３ )CH ２ CH ３ , C(=O)NHCH(CH ２ CH ３ )CH ２ CH ３ C(=O)alkyl, C(=O)haloalkyl, C(=O)CH ３ , C(=O)Et, C(=O)C=CCH ３ , C(=O) C≡C, C(=O)N(CH ３ )CH ３ And R ３１ ~R ３４ (At least one of them is C≡C or C≡C-TMS); 【Transformation 5】 (In the formula, R ４１ ~R ４４ These are independently H, ethynyl, trimethylsilyl-ethynyl, and C １ ~C ６ Alkoxy, C １ ~C ６ Thioalkyl, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkenil, C ３ ~C ６ Cycloalkenyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkenil, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, benzyl, CH(OH)CH ３ , C(=O)NH ２ CO ２ H, CO ２ Me, CO ２ Et, C(=O)H, CH ２ OH, halogen, C(=O)NHCH ２ C≡C, C(=O)NHCH(CH ３ )C≡C, C(=O)NHCH(CH ２ CH ３ )C≡C, C≡N, C(=O)NHC(CH ３ ) (CH ３ )C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH ３ )CH ３ , C(=O)NHCH(CH ３ )CH ２ CH ３ , C(=O)NHCH(CH ２ CH ３ )CH ２ CH ３ C(=O)alkyl, C(=O)haloalkyl, C(=O)CH ３ , C(=O)Et, C(=O)C=CCH ３ , C(=O) C≡C, C(=O)N(CH ３ )CH ３ And R ４１ ~R ４４ (At least one of them is C≡C or C≡C-TMS); 【Transformation 6】 (In the formula, R ５１ , R ５２ , and R ５３ These are independently H, ethynyl, trimethylsilyl-ethynyl, and C １ ~C ６ Alkoxy, C １ ~C ６ Thioalkyl, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkenil, C ３ ~C ６ Cycloalkenyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkenil, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, benzyl, CH(OH)CH ３ , C(=O)NH ２ CO ２ H, CO ２ Me, CO ２ Et, C(=O)H, CH ２ OH, halogen, C(=O)NHCH ２ C≡C, C(=O)NHCH(CH ３ )C≡C, C(=O)NHCH(CH ２ CH ３ )C≡C, C≡N, C(=O)NHC(CH ３ ) (CH ３ )C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH ３ )CH ３ , C(=O)NHCH(CH ３ )CH ２ CH ３ , C(=O)NHCH(CH ２ CH ３ )CH ２ CH ３ C(=O)alkyl, C(=O)haloalkyl, C(=O)CH ３ , C(=O)Et, C(=O)C=CCH ３ , C(=O) C≡C, C(=O)N(CH ３ )CH ３ And R ５１ , R ５２ , or R ５３ (At least one of them is C≡C or C≡C-TMS); 【Transformation 7】 , and (In the formula, R ６１ , R ６２ , and R ６３ These are independently H, ethynyl, trimethylsilyl-ethynyl, and C １ ~C ６ Alkoxy, C １ ~C ６ Thioalkyl, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkenil, C ３ ~C ６ Cycloalkenyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkenil, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, benzyl, CH(OH)CH ３ , C(=O)NH ２ CO ２ H, CO ２ Me, CO ２ Et, C(=O)H, CH ２ OH, halogen, C(=O)NHCH ２ C≡C, C(=O)NHCH(CH ３ )C≡C, C(=O)NHCH(CH ２ CH ３ )C≡C, C≡N, C(=O)NHC(CH ３ ) (CH ３ )C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH ３ )CH ３ , C(=O)NHCH(CH ３ )CH ２ CH ３ , C(=O)NHCH(CH ２ CH ３ )CH ２ CH ３ C(=O)alkyl, C(=O)haloalkyl, C(=O)CH ３ , C(=O)Et, C(=O)C=CCH ３ , C(=O) C≡C, C(=O)N(CH ３ )CH ３ And R ６１ , R ６２ , or R ６３ (At least one of them is C≡C or C≡C-TMS); 【Transformation 8】 (In the formula, R ７１ , R ７２ , R ７３ , and R ７４ These are independently H, ethynyl, trimethylsilyl-ethynyl, and C １ ~C ６ Alkoxy, C １ ~C ６ Thioalkyl, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkenil, C ３ ~C ６ Cycloalkenyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkenil, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, benzyl, CH(OH)CH ３ , C(=O)NH ２ CO ２ H, CO ２ Me, CO ２ Et, C(=O)H, CH ２ OH, halogen, C(=O)NHCH ２ C≡C, C(=O)NHCH(CH ３ )C≡C, C(=O)NHCH(CH ２ CH ３ )C≡C, C≡N, C(=O)NHC(CH ３ ) (CH ３ )C≡C, C(=O)NH-cyclopropyl, C(=O)NH-cyclobutyl, C(=O)NH-cyclopentyl, C(=O)NH-cyclohexyl, C(=O)NHCH(CH ３ )CH ３ , C(=O)NHCH(CH ３ )CH ２ CH ３ , C(=O)NHCH(CH ２ CH ３ )CH ２ CH ３ C(=O)alkyl, C(=O)haloalkyl, C(=O)CH ３ , C(=O)Et, C(=O)C=CCH ３ , C(=O) C≡C, C(=O)N(CH ３ )CH ３ And R ７１ , R ７２ , R ７３ , or R ７４ At least one of them is C≡C or C≡C-TMS).

2. The aforementioned compound, 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 A composition according to claim 1, selected from the group consisting of the following.

3. The aforementioned compound, 【Chemistry 12】 A composition according to claim 1, selected from the group consisting of the following.

4. The composition according to claim 1, further comprising an ammonia source.

5. The composition according to claim 4, wherein the ammonia source is selected from the group consisting of anhydrous ammonia, ammonium nitrate, ammonium urea nitrate, manure, and mixtures thereof.

6. The composition according to claim 1, further comprising the second nitrification-inhibiting compound according to claim 1.

7. A method for reducing soil nitrification, comprising applying a composition according to any one of claims 1 to 6 to the soil.

8. The method according to claim 7, wherein the composition and the ammonia source are applied simultaneously.

9. The method according to claim 7, wherein the composition and the ammonia source are applied sequentially.

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